US2002004511A1PendingUtilityA1
Thiophene derivatives useful as anticancer agents
Priority: Jun 28, 2000Filed: Jun 25, 2001Published: Jan 10, 2002
Est. expiryJun 28, 2020(expired)· nominal 20-yr term from priority
C07D 495/04
39
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Claims
Abstract
The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts and hydrates thereof, wherein X, Y, R 1 , R 2 and R 11 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formula 1.
Claims
exact text as granted — not AI-modified1 . A compound of the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is N, CH or C—CN;
Y is N, CH, CF, or N→O;
R 1 is H;
R 2 is 5 to 13 membered heterocyclic, wherein said R 2 group is optionally substituted by 1 to 5 R 5 substituents,
each R 5 is independently selected from halo, cyano, trifluoromethoxy, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , —OR 9 , —SO 2 NR 6 R 7 , —NR 9 SO 2 NR 6 R 7 , —SO 2 R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —S(O) j (C 1 -C 6 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) j NR 7 (CH 2 ) q S(O) j (C 1 -C 6 alkyl), —(CH 2 ) j NR 7 (CH 2 ) t R 6 , —SO 2 (CH 2 ) t (C 6 -C 10 aryl), and —SO 2 (CH 2 ) t (5 to 10 membered heterocyclic), wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —(CH 2 ) t OR 9 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (C 6 -C 10 cycloalkyl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6 and R 7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —O(C 1 -C 10 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is selected from the group consisting of imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl, wherein said imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl are optionally substituted by 1 to 5 R 6 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol;
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine; or
2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
2 . The compound of claim 1 , wherein R 11 is imidazolyl, oxazolyl or thiazolyl, wherein said imidazolyl, oxazolyl and thiazolyl are optionally substituted by 1 to 5 R 5 groups.
3 . The compound of claim 2 , wherein said imidazolyl, oxazolyl and thiazolyl are optionally substituted by 1 to 5 R 5 groups, each R 5 is independently selected from cyano, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —(CH 2 ) t (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) j NR 7 (CH 2 ) t R 6 , wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
4 . The compound of claim 3 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
5 . The compound of claim 4 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
6 . The compound of claim 1 , wherein R 2 is a group of the formula
wherein X 2 is —S—, —N(R 6 )— or O, and X 3 , X 4 , X 5 , X 6 , and Z is N or CH, the dashed line in formula 2 represents an optional double bond, and the above R 2 groups of formulas 2, 4 and 6 are optionally substituted by 1 to 5 R 5 substituents and the R 2 groups of formulas 3 and 5 are optionally substituted by 1 to 3 R 5 substituents.
7 . The compound of claim 6 , wherein said R 2 group is a group of formula 2, wherein said group is optionally substituted by 1 to 3 R 5 substituents.
8 . The compound of claim 1 , wherein said compound is selected from the group consisting of:
{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-morpholin-4-yl-methanone; {1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-(4-methyl-piperazin-1-yl)-methanone; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid dimethylamide; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid methylamide; 2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propane-1,2-diol; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid amide; 2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol; (2-methyl-1H-indol-5-yl)-(2-4 pyrrolidin-1-ylmethyl-thiazole-2-yl)-thieno[3,2-b]pyridin-7-yl)-amine; pharmaceutically acceptable salts of said compounds; solvates of said compounds; and prodrugs of said compounds.
9 . A compound of the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is N, CH or C—CN;
Y is N, CH, CF, or N→O;
R 1 is H;
R 2 is 5 to 13 membered heterocyclic, wherein said R 2 group is optionally substituted by 1 to 5 R 5 substituents,
each R 5 is independently selected from halo, cyano, trifluoromethoxy, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , —OR 9 , —SO 2 NR 6 R 7 , —NR 9 SO 2 NR 6 R 7 , —SO 2 R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —S(O) j (C 1 -C 6 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) j NR 7 (CH 2 ) q S(O) j (C 1 -C 6 alkyl), —(CH 2 ) j NR 7 (CH 2 ) t R 6 , —SO 2 (CH 2 ) t (C 6 -C 10 aryl), and —SO 2 (CH 2 ) t (5 to 10 membered heterocyclic), wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —(CH 2 ) t OR 9 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), (CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (C 6 -C 10 cycloalkyl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6 and R 7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, or with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —O(C 1 -C 10 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is selected from the group consisting of imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl, wherein said imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl are optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol;
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine;
2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol;
[2-(2-Ethoxy-thiazol-5-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-[2-(4-methyl-thiazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-amine;
[2-(3-Methoxymethyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
{2-[5-(4-Methoxy-phenyl)-oxazol-2-yl}-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine; or
2-{4-Methyl-2-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
10 . The compound of claim 9 , wherein R 11 is imidazolyl, oxazolyl or thiazolyl, wherein said imidazolyl, oxazolyl and thiazolyl are optionally substituted by 1 to 5 R 5 groups.
11 . The compound of claim 10 , wherein said imidazolyl, oxazolyl and thiazolyl are optionally substituted by 1 to 5 R 5 groups, each R 5 is independently selected from cyano, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —(CH 2 ) t (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) j NR 7 (CH 2 ) t R 6 , wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
12 . The compound of claim 11 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
13 . The compound of claim 12 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
14 . The compound of claim 9 , wherein R 2 is a group of the formula
wherein X 2 is —S—, —N(R 6 )— or O, and X 3 , X 4 , X 5 , X 6 , and Z is N or CH, the dashed line in formula 2 represents an optional double bond, and the above R 2 groups of formulas 2, 4 and 6 are optionally substituted by 1 to 5 R 5 substituents and the R 2 groups of formulas 3 and 5 are optionally substituted by 1 to 3 R 5 substituents.
15 . The compound of claim 14 , wherein said R 2 group is a group of formula 2, wherein said group is optionally substituted by 1 to 3 R 5 substituents.
16 . The compound of claim 9 , wherein said compound is selected from the group consisting of:
{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-morpholin-4-yl-methanone; {1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-(4-methyl-piperazin-1-yl)-methanone; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid dimethylamide; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid methylamide; 2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propane-1,2-diol; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid amide; 2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol; (2-methyl-1H-indol-5-yl)-(2-4 pyrrolidin-1-ylmethyl-thiazole-2-yl)-thieno[3,2-b]pyridin-7-yl)-amine; pharmaceutically acceptable salts of said compounds; solvates of said compounds; and prodrugs of said compounds.
17 . A compound of the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is CH;
Y is N;
R 1 is H;
R 2 is 5 to 13 membered heterocyclic, wherein said R 2 group is optionally substituted by 1 to 5 R 5 substituents,
each R 5 is independently selected from cyano, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , —NR 9 SO 2 NR 6 R 7 , —SO 2 R 6 , C 1 -C 6 alkyl, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —(CH 2 ) t (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) j NR 7 (CH 2 ) t R 6 , wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 8 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (C 6 -C 10 cycloalkyl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6 and R 7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —O(C 1 -C 10 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is selected from the group consisting of imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl, wherein said imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl are optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol;
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine; or 2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
18 . The compound of claim 17 , wherein each R 5 is independently selected from cyano, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, (CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —(CH 2 ) t (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) j NR 7 (CH 2 ) t R 6 , wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
19 . The compound of claim 18 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
20 . The compound of claim 19 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
21 . The compound of claim 17 , wherein R 2 is a group of the formula
wherein X 2 is —S—, —N(R 6 )— or O, and X 3 , X 4 , X 5 , X 6 , and Z is N or CH, the dashed line in formula 2 represents an optional double bond, and the above R 2 groups of formulas 2, 4 and 6 are optionally substituted by 1 to 5 R 5 substituents and the R 2 groups of formulas 3 and 5 are optionally substituted by 1 to 3 R 5 substituents.
22 . The compound of claim 21 , wherein R 2 group is a group of formula 2, wherein said group is optionally substituted by 1 to 3 R 5 substituents.
23 . The compound of claim 17 , wherein said compound is selected from the group consisting of:
{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-morpholin-4-yl-methanone; {1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-(4-methyl-piperazin-1-yl)-methanone; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid dimethylamide; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid methylamide; 2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propane-1,2-diol; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid amide; 2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol4-yl}-propan-2-ol; (2-methyl-1H-indol-5-yl)-(2-4 pyrrolidin-1-ylmethyl-thiazole-2-yl)-thieno[3,2-b]pyridin-7-yl)-amine; pharmaceutically acceptable salts of said compounds; solvates of said compounds; and prodrugs of said compounds.
24 . A compound of the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is CH;
Y is N;
R 1 is H;
R 2 is 5 to 13 membered heterocyclic, wherein said R 2 group is optionally substituted by 1 to 5 R 5 substituents,
each R 5 is independently selected from cyano, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , —NR 9 SO 2 NR 6 R 7 , —SO 2 R 6 , C 1 -C 6 alkyl, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —(CH 2 ) t (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) j NR 7 (CH 2 ) t R 6 , wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (C 6 -C 10 cycloalkyl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6 and R 7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —O(C 1 -C 10 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is selected from the group consisting of imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl, wherein said imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl and thiadiazolyl are optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol;
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine;
2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol;
[2-(2-Ethoxy-thiazol-5-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-[2-(4-methyl-thiazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-amine;
[2-(3-Methoxymethyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
{2-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-thieno[3,2-b]pyridin-7-yl}-(2-methyl-1H-indol-5-yl)-amine; or
2-{4-Methyl-2-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
25 . The compound of claim 24 , wherein said imidazolyl, oxazolyl and thiazolyl are optionally substituted by 1 to 5 R 5 groups, each R 5 is independently selected from cyano, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —(CH 2 ) j O(CH 2 ) q NR 6 R 7 , —(CH 2 ) t O(CH 2 ) q OR 9 , —(CH 2 ) t OR 9 , —(CH 2 ) t (5 to 10 membered heterocyclic), —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) j NR 7 (CH 2 ) q NR 6 R 7 , —(CH 2 ) j NR 7 CH 2 C(O)NR 6 R 7 , —(CH 2 ) j NR 7 (CH 2 ) q NR 9 C(O)R 8 , —(CH 2 ) j NR 7 (CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) j NR 7 (CH 2 ) t R 6 , wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the —(CH 2 ) q — and —(CH 2 ) t — moieties of the foregoing R 5 groups optionally include a carbon-carbon double or triple bond where t is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
26 . The compound of claim 25 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
27 . The compound of claim 26 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
28 . The compound of claim 24 , wherein R 2 is a group of the formula
wherein X 2 is —S—, —N(R 6 )— or O, and X 3 , X 4 , X 5 , X 6 , and Z is N or CH, the dashed line in formula 2 represents an optional double bond, and the above R 2 groups of formulas 2, 4 and 6 are optionally substituted by 1 to 5 R 5 substituents and the R 2 groups of formulas 3 and 5 are optionally substituted by 1 to 3 R 5 substituents.
29 . The compound of claim 28 , wherein R 2 group is a group of formula 2, wherein said group is optionally substituted by 1 to 3 R 5 substituents.
30 . The compound of claim 24 , wherein said compound is selected from the group consisting of:
{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-morpholin-4-yl-methanone; {1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-(4-methyl-piperazin-1-yl)-methanone; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid dimethylamide; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid methylamide; 2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propane-1,2-diol; 1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazole-2-carboxylic acid amide; 2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol; (2-methyl-1H-indol-5-yl)-(2-4 pyrrolidin-1-ylmethyl-thiazole-2-yl)-thieno[3,2-b]pyridin-7-yl)-amine; pharmaceutically acceptable salts of said compounds; solvates of said compounds; and prodrugs of said compounds.
31 . A compound of claim 1 , having the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is CH;
Y is N;
R 1 is H;
R 2 is
X 2 is —N(R 6 )—, the dashed line in formula 2 represents an optional double bond, and the above R 2 group of formula 2 is optionally substituted by 1 to 5 R 5 substituents;
each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (C 6 -C 10 cycloalkyl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6 and R 7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —O(C 1 -C 10 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is selected from the group consisting of imidazolyl, oxazolyl, or thiazolyl, wherein said imidazolyl, oxazolyl, or thiazolyl are optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol;
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine; or
2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
32 . The compound of claim 31 , wherein R 11 is thiazolyl and said thiazolyl is optionally substituted by 1 to 5 R 5 groups.
33 . The compound of claim 32 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
34 . The compound of claim 31 , wherein R 2 is 2-methyl-1H-indol-5-ylamino.
35 . A compound of claim 1 , having the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is CH;
Y is N:
R 1 is H;
R 2 is
X 2 is —N(R 6 )—, the dashed line in formula 2 represents an optional double bond, and the above R 2 group of formula 2 is optionally substituted by 1 to 5 R 5 substituents;
each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , —NR 6 R 7 , —OR 9 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (C 6 -C 10 cycloalkyl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6 and R 7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —O(C 1 -C 10 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is selected from the group consisting of imidazolyl, oxazolyl, or thiazolyl, wherein said imidazolyl, oxazolyl, or thiazolyl are optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol;
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine;
2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol;
[2-(2-Ethoxy-thiazol-5-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-[2-(4-methyl-thiazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-amine;
[2-(3-Methoxymethyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
{2-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-thieno[3,2-b]pyridin-7-yl}-(2-methyl-1H-indol-5-yl)-amine; or
2-{4-Methyl-2-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
36 . The compound of claim 35 , wherein R 11 is thiazolyl and said thiazolyl is optionally substituted by 1 to 5 R 5 groups.
37 . The compound of claim 36 , wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6, the —(CH 2 ) t — moiety of the foregoing R 5 group optionally includes a carbon-carbon double or triple bond when t is an integer from 2 to 6, and the alkyl and heterocyclic moieties of the foregoing R 5 groups are optionally substituted by 1 to 3 substituents independently selected from —C(O)R 8 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —(CH 2 ) t NR 6 R 7 , C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6.
38 . The compound of claim 39 , wherein R 2 is 2-methyl-1H-indol-5-ylamino.
39 . The compound of claim 1 , having the formula 1
or a pharmaceutically acceptable salt, prod rug or hydrate thereof,
X is CH;
Y is N;
R 1 is H;
R 2 is
wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (C 6 -C 10 cycloalkyl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6 and R 7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, trifluoromethyl, —C(O)R 8 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —NR 9 R 10 , C 1 -C 6 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5 to 10 membered heterocyclic), —(CH 2 ) t O(CH 2 ) q OR 9 , and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —O(C 1 -C 10 alkyl), —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is selected from the group consisting of imidazolyl, oxazolyl, or thiazolyl, wherein said imidazolyl, oxazolyl, or thiazolyl are optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol;
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine; or
2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
40 . The compound of claim 39 , wherein each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6 with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen.
41 . The compound of claim 40 , wherein R 11 is thiazolyl and wherein said thiazolyl is optionally substituted by 1 to 5 R 5 groups.
42 . A compound of claim 1 , having the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is CH;
Y is N;
R 1 is H;
R 2 is
wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
wherein each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is thiazolyl wherein said thiazolyl is optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
(2-Methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine; or
2-{2-[7-(2-Methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol.
43 . The compound of claim 1 , having the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is CH;
Y is N;
R 1 is H;
R 2 is
wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
wherein each R 6 and R 7 is independently selected from H, C 1 -C 10 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is oxazolyl, wherein said oxazolyl is optionally substituted by 1 to 5 R 5 groups.
44 . A compound of claim 1 , having the formula 1
or a pharmaceutically acceptable salt, prodrug or hydrate thereof,
X is CH;
Y is N;
R 1 is H;
R 2 is
wherein each R 5 is independently selected from —C(O)R 8 , —C(O)NR 6 R 7 , C 1 -C 6 alkyl, —C(O)(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
wherein each R 6 and R 7 is independently selected from H, C 1 -C 6 alkyl, —(CH 2 ) t (5 to 10 membered heterocyclic), and —(CH 2 ) t OR 9 , wherein t is an integer from 0 to 6, with the proviso that where R 6 and R 7 are both attached to the same nitrogen, then R 6 and R 7 are not both bonded to the nitrogen directly through an oxygen;
each R 8 is independently selected from H, C 1 -C 10 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), and —(CH 2 ) t (5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R 9 and R 10 is independently selected from H and C 1 -C 6 alkyl; and,
R 11 is imidazolyl wherein said imidazolyl is optionally substituted by 1 to 5 R 5 groups with the proviso that compound 1 is not
[2-(3-Methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine;
2-{1-Methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol; or
[2-(1-Methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine.
45 . A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
46 . The pharmaceutical composition of claim 45 , wherein said hyperproliferative disorder is cancer.
47 . The pharmaceutical composition of claim 46 , wherein said cancer is brain, lung, kidney, renal, ovarian, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, gynecological, prostate, colorectal or thyroid cancer.
48 . The pharmaceutical composition of claim 45 , wherein said hyperproliferative disorder is noncancerous.
49 . The pharmaceutical composition of claim 48 , wherein said disorder is a benign hyperplasia of the skin or prostate.
50 . A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of claim 1 in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens, and a pharmaceutically acceptable carrier.
51 . A pharmaceutical composition for the treatment of pancreatitis or kidney disease in a mammal which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
52 . A pharmaceutical composition for the blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
53 . A pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
54 . The pharmaceutical composition of claim 53 wherein said disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
55 . A method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 .
56 . The method of claim 55 wherein said hyperproliferative disorder is cancer.
57 . The method of claim 56 wherein said cancer is brain, lung, squamous cell, renal, kidney, ovarian, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, gynecological or thyroid cancer.
58 . The method of claim 55 wherein said hyperproliferative disorder is noncancerous.
59 . The method of claim 58 wherein said disorder is a benign hyperplasia of the skin or prostate.
60 . A method for the treatment of a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
61 . A method of treating pancreatitis or kidney disease in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 .
62 . A method of preventing blastocyte implantation in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 .
63 . A method for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 .
64 . The method of claim 63 , wherein said disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.Join the waitlist — get patent alerts
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